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Molecular Mechanisms of Renal Tissue Repair in Survival from Acute Renal Tubule Necrosis: Role of ERK1/2 PathwayDepartment of Toxicology, School of Pharmacy, The University of Louisiana at Monroe, Louisiana, USA
Department of Toxicology, School of Pharmacy, The University of Louisiana at Monroe, Louisiana, USA
Syngenta, Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire, UK
Laboratory of Experimental Pathology, NIEHS, Research Triangle Park, North Carolina, USA
Department of Toxicology, School of Pharmacy, The University of Louisiana at Monroe, Louisiana, USA, mehendale{at}ulm.edu
Our earlier studies with S-(1,2-dichlorovinyl)-L-cysteine (DCVC) showed that prior administration of a low priming dose of 15 mg/kg, IP to mice, given 72 hours before administration of a normally lethal dose of DCVC (75 mg/kg, IP) led to renal tubule necrosis, however sustained renal tubule regeneration was observed and these mice recovered from renal failure and survived. The objective of the present study was to investigate the role of extracellular signal-regulated kinase (ERK) pathway in this autoprotection model. Following the priming dose of DCVC, IL-6 protein and mRNA increased markedly as early as 1 hour after dosing, peaking at 3 hours with a 1.5-fold increase in plasma. Immunocytochemistry on kidney sections using specific antibodies against TGF-
Key Words: Renal tubular necrosis • cytokines • ERK1/2 pathway • tissue repair • growth factors • nephrotoxicity.
Toxicologic Pathology, Vol. 31, No. 6,
604-618 (2003) This article has been cited by other articles:
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, HB-EGF, EGFr, IGF-1R β, Grb-2, and phospho-p44/42 MAP kinase (ERK1/2) revealed a significantly higher staining of these molecules 3 to 72 hours after dosing, indicating up regulation of the ERK pathway. Following a lethal dose of DCVC (75 mg/kg) the early increase in these signaling molecules was not sustained, being markedly reduced 24 and 36 hours after dosing, leading to inhibition of S-phase DNA synthesis, cell division and renal tubule repair. In contrast, prior treatment with a low dose of DCVC, followed by a high dose led to a sustained stimulation of the renal ERK pathway, renal tubule regeneration and recovery from acute renal failure. These results suggest that a sustained activation of the ERK1/2 pathway may be a key factor in enabling a continued renal tubule repair and hence protection from the progressive phase of DCVC-induced acute renal tubular necrosis in the mouse. 
